The emerging role of physiologically-based pharmacokinetic/biopharmaceutics modeling in formulation development

Abstract

Computer-based (in silico) modeling & simulation tools have been embraced in different fields of pharmaceutics for a variety of applications. Among these, physiologically-based pharmacokinetic/biopharmaceutics modeling (PBPK/PBBM) emerged as a particularly useful tool in formulation development. PBPK/PBBM facilitated strategies have been increasingly evaluated over the past few years, as demonstrated by several reports from the pharmaceutical industry, and a number of research and review papers on this subject. Also, the leading regulatory authorities have recently issued guidance on the use of PBPK modeling in formulation design. In silico PBPK models can comprise different dosing routes (oral, intraoral, parenteral, inhalation, ocular, dermal etc.), although the majority of published examples refer to modeling of oral drugs performance. In order to facilitate the use of PBPK modeling tools, a couple of companies have launched commercially available software such as GastroPlus™, Simcyp™ PBPK Simulator and PK-Sim®. This paper highlights various application fields of PBPK/PBBM modeling, along with the basic principles, advantages and limitations of this approach, and provides relevant examples to demonstrate the practical utility of modeling & simulation tools in different stages of formulation development.

Računarski podržano (in silico) modelovanje se danas koristi u različitim oblastima farmaceutskih nauka, sa širokom paletom primene. Kao jedan od in silico alata, fiziološki zasnovano farmakokinetičko/biofarmaceutsko modelovanje (PBPK/PBBM) se pokazalo posebno korisnim u razvoju farmaceutskih preparata. Strategije zasnovane na PBPK/PBBM modelovanju se poslednjih godina sve više razmatraju, što se vidi iz izveštaja farmaceutskih kompanija i velikog broja publikovanih istraživačkih i revijalnih radova na ovu temu. Takođe, vodeće regulatorne agencije su nedavno izdale vodiče koji se odnose na primenu PBPK modelovanja u razvoju farmaceutskih preparata. In silico PBPK modelovanje je primenjivo za različite puteve primene leka (peroralni, (intra)oralni, parenteralni, inhalacioni, okularni, dermalni itd), mada se najveći broj primera iz literature odnosi na modelovanje bioperformansi peroralno primenjenih lekova. Kako bi olakšale primenu PBPK modelovanja, nekoliko kompanija je razvilo komercijalno dostupne programske pakete, kao što su GastroPlus™, Simcyp™ PBPK Simulator i PK-Sim®. U ovom radu su istaknute različite mogućnosti primene PBPK/PBBM modelovanja, uključujući osnovne principe, prednosti i ograničenja. Takođe, prikazani su odgovarajući primeri koji opisuju praktičnu primenu modelovanja i simulacija u različitim fazama razvoja leka.